WO2008131567A1

WO2008131567A1 - Solvent-free crystalline form of naltrexone

Info

Publication number: WO2008131567A1
Application number: PCT/CH2007/000203
Authority: WO
Inventors: Ulrich Weigl; Ulf KÖTZ
Original assignee: Cilag Ag
Priority date: 2007-04-27
Filing date: 2007-04-27
Publication date: 2008-11-06
Also published as: US20100210675A1; EP2150554A1

Abstract

Solvent-free crystalline polymorphic form of naltrexone, characterized in that it has the XRD data listed in Table 1, and a method for the preparation of this polymorphic form; and a method for converting this polymorphic form of naltrexone into a known polymorphic form of naltrexone.

Description

Solvent-free crystalline form of naltrexone

The present invention relates to a novel solvent-free crystalline polymorphic form of naltrexone and to processes for producing this polymorphic form.

Naltrexone and its derivatives and salts, for example naltrexone hydrochloride, N-methylnaltrexone bromide (methylnaltrexone) or naltrexone methobromide, are known pharmaceutically active compounds, which are used in particular for reducing the psychological dependence in drug abuse. The compound naltrexone as free base corresponds to the chemical formula:

J "5 N altrexo n

Numerous polymorphic forms for the free base of naltrexone, in particular solvates, and their preparation are described in WO 2004/108084.

20

It has now been found that from Esterverbindungen, especially from (Ci-C ₈₎ alkyl acetates, (C ₁ -C ₈₎ Alkylbutyraten and / or (C ₁ -C ₈₎ - alkyl benzoates, a new solvent-free crystalline polymorphic form of naltrexone by crystallization 5 can be obtained. This new polymorphic form of naltrexone has surprising and positive properties. The term "solvent-free form" means that this form is neither a solvate nor a hydrate. 0 The surprising and positive properties of this new polymorphic form include the fact that it also crystallizes from highly colored reaction solutions as a colorless product in very high HPLC purity and has high stability. The crystallization is usually simple and with high volume and reaction yields. The dynamic vapor absorption (dynamic vapor sorption) also shows only a very low uptake of water even under high hygroscopic conditions, which is of particular importance for the practical processing and use of the modification according to the invention, whereby any water taken up is very easily removed or can be dried out. The new polymorphic form is therefore particularly well suited for formulations of naltrexone in which, according to customary customer specifications, the water content in the end product must be as small as possible.

The present invention is defined in the claims. In particular, the present invention relates to a novel solventless crystalline polymorphic form of naltrexone which is characterized by having the following XRD data listed in Table 1:

Table 1

As starting material, naltrexone of any purity can be used. For very impure crude products (purity <80%), the crystallization may need to be repeated.

For the crystallization, the naltrexone starting product or the nalrexone crude product is dissolved in the solvent at elevated temperature, preferably at the reflux temperature of the particular solvent, in a concentration of preferably 1 (one) gram / 100 grams to 50 grams / 100 grams of the solvent. preferably stirring at the solution temperature for 10 minutes to 24 hours. Then allowed to cool to room temperature, wherein the inventive polymorphic form crystallized. One purpose preferably cools the solution to a tem- perature ranging from room temperature about 20 ⁰ C to -2O ⁰ C.

In this sense, the present invention relates to a process for the preparation of a solvent-free crystalline polymorphic form of naltrexone, which comprises using as starting material any naltrexone, preferably having a purity of at least 80% (purity ≥80%) in a solvent, containing at least one ester compound or a mixture of ester compounds, at elevated temperature, preferably at reflux temperature of the respective solvent, dissolves, preferably stirred at the solution temperature for ten minutes to 24 hours, and then allowed to cool, wherein the inventive polymorphic form crystallized.

Preferably, the solvent contains at least 80% by weight, preferably at least 90% by weight, of an ester compound or a mixture of ester compounds.

Preferably, the Natrexon starting material is dissolved in the solvent in a concentration of preferably 1 gram / 100 grams to 50 grams / 100 grams of the solvent. The mixture is preferably stirred at the solution temperature for 30 minutes to 12 hours and then allowed to cool to a temperature preferably in the range of about 2O ⁰ C to -20 ° C.

The solvents used for the crystallization according to the invention are ester compounds, in particular (C 1 -C ₈ ) alkyl acetates, preferably methyl acetate, ethyl acetate, propyl acetate, butyl acetate; (C ₁ -C ₈ ) -alkyl butyrates, preferably methyl butyrate, ethyl butyrate, propyl butyrate, butyl butyrate; (C 1 -C ₈ ) alkyl benzoates, preferably methyl benzoate, ethyl benzoate, propyl benzoate, butyl benzoate. Preference is given to using methyl acetate, ethyl acetate, propyl acetate, butyl acetate; Methyl butyrate, ethyl butyrate, methyl benzoate, ethyl benzoate, or a mixture of these compounds, preferably methyl acetate, ethyl acetate, ethyl butyrate, or a mixture of these compounds.

The invention further relates to a process for the conversion of the polymorphic form according to the invention into a polymorphic form which is known per se, which comprises reacting the polymorphic form according to the invention in an alcohol, preferably a (C 1 -C ₄ ) -alcohol, preferably methanol, Ethanol, propanol, butanol or in a ketone, preferably acetone, or in a mixture of these compounds, preferably in methanol, ethanol or acetone, or in a mixture of these compounds, as long as aufschlämmt until the inventive form has converted into the known polymorph. Such a known form is described for example in US 2006/0142320, Figure B. This forms a suspension in the slurry.

Preferably, it is slurried at a slightly elevated temperature, preferably at a temperature in the range of -20 ° C to + 4O ⁰ C, for a period of about 10 minutes to 24 hours, wherein the known per se forms virtually quantitative. Preferably, the mixture is cooled for isolating the product formed domestic product to at least room temperature, preferably to a temperature ranging from room temperature (about 20 ⁰ C) to -2O ⁰ C decreases. This process also offers the possibility of producing a polymorph which is known per se, by first preparing the polymorph according to the invention and then converting this into the polymorph known per se by precipitation, for example in methanol.

This process offers the particular advantage of producing the polymorph, which is known per se, in a very gentle manner and in a very pure form, without any partial decomposition of the naltrexone being observed, which is the customary procedure

Recrystallization of naltrexone due to the application of elevated temperature is the case.

The present invention also relates to the use of the polymorphs according to the invention as remedies and the

Use of the polymorphs produced according to the invention for

Production of a pharmaceutically administrable remedy, in particular for the reduction of psychological dependence

Substance abuse.

The following examples illustrate the invention without limiting it.

Example 1 10 g of crude naltrexone are suspended in 50 g of ethyl acetate and heated to reflux. After 1 hour (h) reflux, the resulting solution is cooled within 3-4 h to ^{0 0} C to 4 ° C and stirred for a further 1-2 h. The crystalline solid is filtered off with suction and dried in vacuo. 8g naltrexone are isolated. The XRD data: NTX (Naltrexone) 985-89. D are in

Figure 1 shown. The obtained XRD data correspond to the values listed in Table 1.

Example 2 2g of crude naltrexone are suspended in 12g of methyl acetate and heated to reflux until all naltrexone is dissolved. The resulting solution is cooled to 20-25 ° C. within ¹ h. Of the crystalline solid is filtered off and dried in vacuo. There will be 1. 0g naltrexone isolated. The obtained XRD data basically correspond to the values listed in Table 1.

Example 3

40g of crude naltrexone are suspended in 136g of methanol; then the mixture is stirred at 15 ⁰ C for 3h. The mixture is then stirred at 0 ⁰ C for 2 h. The crystalline solid is filtered off with suction and dried in vacuo. 37.5 g of the known naltrexone are isolated, as described in US 2006/0142320, Figure B.

Claims

claims

Solvent-free crystalline polymorphic form of naltrexone, characterized in that it has the following XRD data listed in Table 1:

Table 1

2. A process for the preparation of the polymorphic form of naltrexone according to claim 1, characterized in that as starting material any naltrexone, preferably having a purity of at least 80% (purity ≥80%) in a solvent containing at least one ester compound or a mixture of ester compounds, at elevated temperature, preferably at the reflux temperature of the respective solvent, is dissolved, preferably stirred at the solution temperature for ten minutes to 24 hours, and then allowed to cool, wherein the polymorphic form of naltrexone crystallized out according to claim 1.

3. The method according to claim 1, characterized in that the solvent contains at least 80 wt .-%, preferably at least 90 wt .-%, of an ester compound or a mixture of ester compounds.

4. The method according to claim 2 or 3, characterized in that one solves the Natrexon starting material in the solvent in a concentration of 1 gram / 100 grams to 50 grams / 100 grams of the solvent.

5. The method according to any one of claims 2-4, characterized in that stirring is continued at the solution temperature for 30 minutes to 12 hours and then allowed to cool to a temperature in the range of about 2O ⁰ C to -2O ⁰ C.

6. The method according to any one of claims 2-5, characterized in that the solvent used is at least one ester compound which is selected from the group comprising (Ci-C ₈ ) alkyl acetates, preferably methyl acetate, ethyl acetate, propyl acetate, butyl acetate; (C ₁ -C ₈ ) -alkyl butyrates, preferably methyl butyrate, ethyl butyrate, propyl butyrate, butyl butyrate; (C 1 -C ₈ ) alkyl benzoates, preferably methyl benzoate, ethyl benzoate, propyl benzoate, butyl benzoate.

7. The method according to any one of claims 2-6, characterized in that as the solvent methyl acetate, ethyl acetate, propyl acetate, butyl acetate; Methyl butyrate, ethyl butyrate, methyl benzoate, ethyl benzoate, or a mixture of these compounds, preferably methyl acetate, ethyl acetate, ethyl butyrate, or a mixture of these compounds.

8. A process for the conversion of the polymorphic form of naltrexone according to claim 1 into a known polymorphic form, characterized in that the polymorphic form of naltrexone according to claim 1 in an alcohol, preferably a (C ₁ -C ₄ ) -alcohol, preferably methanol, ethanol, propanol, butanol or in a ketone, preferably acetone, or in one Mixture of these compounds, preferably in methanol, ethanol or acetone, or in a mixture of these compounds, as long as aufschlämmt until the inventive form has converted into the known polymorph.

9. The method according to claim 8, characterized in that at a slightly elevated temperature, preferably at a temperature in the range of -20 ° C to +40 ⁰ C, for a period of about 10 minutes to 24 hours, slurries.

10. The method according to any one of claims 8 or 9, characterized in that for the isolation of the product formed at least at room temperature, preferably to a temperature ranging from room temperature to -20 ⁰ C, cooled.

11. Use of the polymorphic form of naltrexone according to claim 1 as a remedy, in particular for the reduction of mental dependence in drug abuse.

12. Use of the polymorphic form of naltrexone according to

Claim 1 for the preparation of a pharmaceutically available remedy, in particular effective for reducing the mental dependence on drug abuse.